Abstract Elevated IOP is the major risk factor in glaucoma, a neurodegenerative disorder affecting 80 million people worldwide. Loss of retinal ganglion cells and their axons is the major pathological hallmark of glaucoma, the disease facilitated by mechanical damage neuroinflammation and danger signaling. These pathological factors were identified in human glaucoma and in experimental animal models. Our long-term goal is to decrease and, ultimately, prevent vision loss in glaucoma and other retinal and optic nerve pathologies induced by intraocular pressure. Pursuant to our objective, we will characterize a novel pathway that facilitates RGC dysfunction and loss via an interaction between P2X receptors, pannexin1 (Panx1), and inflammasome in the retina. Our project is premised on our preliminary studies that identified two new Panx1 partners that may contribute to RGC toxicity, including upstream regulator P2RX4 and a downstream target, the inflammasome. We found that this signaling cascade activates caspase 1 and 11, the core inflammasome proteases. We will, therefore, test our central hypothesis that the activation of neuronal P2(R)X4 is pivotal for Panx1-mediated neurotoxicity, which triggers inflammasome activation in response to elevated intraocular pressure. Our three specific aims are designed to test this hypothesis and determine whether retinal inflammasome is critical for RGC dysfunction or loss. Specific Aims are designed to: 1) Establish the role of P2X4 receptor in Panx1-mediated loss of RGCs and their axons; 2) Examine the mechanism of P2(R)X4 regulation of Panx1, caspases and the inflammasome, and 3) Determine whether glial ATP release facilitate neuronal inflammasome activation and contribute to Panx1- mediated RGC loss. Significance. This project has a translational potential and is significant because it is developing and testing a novel strategy against inflammation-induced neurodegeneration, implicated in glaucoma, a clinical problem identified by the NIH as a crucial research objective. Preventing vision loss in major blinding pathologies like glaucoma and other ischemic injuries of retina require a comprehensive, knowledge-based therapeutic strategy. This proposal is designed to provide mechanistic understanding for the role of newly discovered non- canonical inflammasome pathway in animal models for these pathologies. This research project will establish the role and feasibility of therapeutic targeting of Panx1-P2X and inflammasome pathways in the chronic ocular hypertension models, relevant to glaucomatous pathology. If successful, the new knowledge of basic biology of inflammation-induced neuronal damage in the retina will help us to identify new targets for rational drug design.